Carbamazepine–Oxcarbazepine

Synthesized in 1953, introduced for trigeminal pain in 1962 and for epilepsy in 1965; approved by the USA FDA since 1976 for the following:

• Epilepsy: Generalized tonic-clonic seizures, partial seizures with complex pathology (psychomotor, temporal), partial seizures with or without generalization, mixed generalized and partial seizures

• Chronic pain: Pain associated to trigeminal and/or glossopharyngeal neuralgia

• CNS disorders: Acute or mixed episodes associated with bipolar I disorder

• Off-label uses: Central and diabetic neuropathic pain; postherpetic neuralgia, phantom limb pain, alcohol withdrawal, preventing relapse in pts with bipolar disorders having a resistance or intolerance to lithium, treatment of manic or hypomanic excitation states, schizophrenia

• Oxcarbazepine (OXC): 10-keto derivative of carbamazepine (CMZ), FDA-approved since 2000 as adjunctive therapy for partial seizures in adults and children >4 y and as monotherapy in adults for partial seizures

Pharmacologic: Clinically significant drug interactions

CNS: Increased sedation, dizziness, and ataxia

CV: Aggravation of Htn, hypotension, CAD, arrhythmias, and rarely AV block

Laboratory: Higher incidence of hyponatremia, aplastic anemia, agranulocytosis, thrombopenia and leukopenia, as well as elevated LFTs and hypothyroidism

The main activated form is the carbamazepine-10, 11 epoxide after transformation by hepatic CYP3A4 and CYP2C8.

Peak plasma concentrations: tablet 2–6 h after ingestion, suspension 1.5 h, extended release 26–96 h. Bioavailability 85–100%, no gender differences, highly lipophilic, protein binding 70–80%, apparent volume of distribution: 0.8–1.5 L/kg. CMZ crosses the placental barrier and passes into breast milk, where it is half as concentrated.

Hepatic biotransformation 98%. T _½ : 10–20 h after 1 dose, 4–12 h after repeated administration (transcriptional upregulation of its own metabolism occurring from day 5 and stabilized between 3–5 wk). SNP in CYP450, in microsomal epoxide hydrolase, in ABCB1 and ABCB2 and Na _V are involved in the variation of metabolism of CMZ.

Mainly metabolized by the CYP3A4 and CYP2C8, others CYP-involved are CYP2B6, CYP3A5, EPHX, and UGT2B7.

• Inhibitors of CMZ: Aprepitant, erythromycin, clarithromycin troleandomycin, verapamil, diltiazem, ketoconazole, fluconazole, itraconazole, voriconazole, acetazolamide, ticlid, nefazodone, valproate, fluvoxamine, fluoxetine, trazodone, olanzapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, and grapefruit juice

• Inducers of CMZ: Glucocorticoids, rifampicin, cotrimoxazole, ritonavir, sertraline, felbamate, cisplatin, doxorubicin, phenytoin, phenobarbital, theophylline, and CMZ autoinduction

• CMZ decreases the plasma concentration of valproic acid, lamotrigine, phenytoin, felbamate, tiagabine, ethosuximide, aripiprazole, lapatinib, itraconazole, tramadol, protease inhibitors, dicumarol, doxycycline, levothyroxine, tricyclic antidepressant, cyclosporine, felodipine, aminosteroid NDMB (pancuronium, vecuronium, rocuronium), and benzodiazepines (interactions compensated by the antiepileptic effect of the added molecule and inductor/inhibitor effects of added molecule). Gabapentin, pregabalin, and levetiracetam are not affected by CMZ. CMZ reduces ethinyl estradiol and progestagen concentrations on the order of 50%.

• OXC: Prodrug converted into active metabolite (S-licarbazepine) in liver by reductase; apparent volume of distribution 49 L, low protein binding fixation (40%), T _max 3–13 h, T _1/2 7–20 h (for the active compound); steady-state 2–3 d; fewer drug-drug interaction (reduced impact on CYP450 system, CYP2C19 ²⁺ , CYP3A4/5 ⁺ ), decreased dihydropyridine calcium antagonist and oral contraceptive

Neurologic:

• Very common: Dizziness, ataxia, drowsiness, fatigue (particularly in elderly)

• Common: Headache, diplopia, accommodation disorders

• Uncommon: Tremor, dystonia, orofacial dyskinesias, nystagmus

• Rare: Oculomotor disturbances, ataxia, speech disorders, agitation, convulsion, suicidal behavior

• Very rare: Neuroleptic malignant syndrome, dysgeusia, aseptic meningitis

Respiratory:

• Rare, pulm hypersensitivity usually associated with eosinophilia and systemic syndrome

CV:

• Negative chronotropic and dromotropic effects (above upper therapeutic level), reduced rise and amplitude on the AP in Purkinje fibers in atrial and ventricular myocardial cells

• Sinus bradycardia, sinoatrial block, and AV block. Hypotension, vasoplegia (poisoning), pulm embolism, CAD and CHF, lymphedema and adenopathy. Very rarely: myocarditis

Hematologic:

• Rare: Leukopenia, thrombocytopenia, pancytopenia, hypogammaglobulinemia. Eosinophilia (aromatic structure associated with DRESS), more frequent in the presence of HLA-A ^∗ 3101 allele in European, Japanese, and Chinese pts.

• Very rarely: Pancytopenia, agranulocytosis, variegate porphyria, acute intermittent porphyria

Dermatologic:

• More common: Maculopapular rash, urticarial, erythema multiforme, and lupus

• Rare: Toxic epidermal necrolysis and Stevens-Johnson syndrome (10 times higher in Thai or Han Chinese pts with the HLA-B ^∗ 1502 allele). Known sensitivity to one anticonvulsant may increase the risk of serious rash with another anticonvulsant.

Metabolic:

• Weight gain, hyponatremia (SIADH, alterations of renal tubular electrolytes transport, V2R-dependent and V2R-independent ways with increased permeability by AQP2 expression, and resetting of osmoreceptors associated to renal impairment)

• Increased T ₄ and free T ₄ , increased TSH (particularly in children)

GI:

• Very common: N/V, dry mouth

• Uncommon: Diarrhea, constipation

• Rare: Abdominal pain

• Very rare: Glossitis, stomatitis, and pancreatitis

GU: Rare: Azotemia, renal failure, increased BUN, acute urinary retention, oliguria, erectile dysfunction

Other:

• Very rare: Allergy, conjunctivitis, leg cramps, hearing loss or hyperacusis, tinnitus

• OXC: 25–35% crossed-hypersensitivity reaction with CMZ; hyponatremia possible but less; SJS and epidermal necrolysis very rare